Volume 7, Issue 9 September 2011
Lamotrigine or Lamictal is one of the most commonly utilized anti-seizure medications in the world. The drug which is considered a second-generation anti-epileptic drug was released in the 1990s and has become one of the more popular choices of medications for a broad variety of seizure and epilepsy types. The following column will help to answer questions that individuals may have regarding the use of lamotrigine or Lamictal in order to better educate individuals with regards to choices of anti-seizure drugs.
Chemistry and Mechanism of Action
Lamotrigine is believed to work via a number of different mechanisms. Its primary mechanism is blockade of sodium channels in nerve cells. It blocks sodium channels activated from depolarized membrane potentials at lower concentrations than those required to elicit blockade from hyperpolarized membrane and occurs at clinically achievable concentrations. Lamotrigine produces a dose-dependent inhibition of high-voltage activated calcium currents possibly through inhibition of pre-synaptic N and P/Q-type calcium channels. Despite its apparent clinical activity in human absence seizures, it does not inhibit low voltage currents mediated by T-type calcium channels. Lamotrigine resembles the mechanisms of phenytoin, but there are striking differences between the two. Lamotrigine is twice as effective in inhibiting the release of glutamate as compared to GABA. Release of excitatory amino acid neurotransmitters such as glutamate and aspartate is blocked during sustained repetitive firing. Animal models also suggest that lamotrigine inhibits ischemia-induced release of excitatory neurotransmitters. Lastly, lamotrigine appears to display only modest inhibition of potassium channels and is a weak inhibitor of 5-HT uptake in humans.
Lamotrigine or Lamictal is an orally administered drug and is available in a variety of dosage strengths including a dispersible tablet. There has been established similarity in the bioequivalence between these different varieties of Lamictal and lamotrigine. The drug is completely absorbed with the bioavailability of 98%. The peak serum concentration is achieved within 1 to 3 hours following oral administration. It has a linear oral absorption with proportionality observed following doses up to 700 mg. A secondary peak in serum concentration can occur 4-6 hours following either oral or IV administration. Food does not affect the absorption of lamotrigine.
An extended release formulation of lamotrigine is available. This formulation is coated and has a modified release core which allows for a gradual release of the medication over 12-15 hours. Studies in patients with epilepsy have demonstrated that the extended release formulation is equivalent to the immediate-release brand product when patients are converted from twice-daily dosing to once-daily dosing of the extended release.
Lamotrigine is systemically absorbed following rectal administration. It is also moderately bound to plasma proteins, about 56%. Lamotrigine’s half life is approximately 24-29 hours when the drug is given in monotherapy. Lamotrigine clearance however is higher in children and lower in the elderly as compared to young adults. Mean lamotrigine oral clearance and elimination half life were 0.64 and 32 hours respectively in children receiving monotherapy. Advancing age has a modest effect in increasing the half life in clearance, particularly in individuals 65 years and older.
Liver disease can influence the pharmacology of Lamictal. There are no significant differences in the clearance of lamotrigine in people who have chronic renal failure. About 17% of the dose of the drug may be removed by dialysis with a reduction in its half life to about 13 hours.
The clearance of lamotrigine does not appear to differ between men and women. Lamotrigine oral clearance can be increased during pregnancy with changes being most evident during the second and third trimester but returns to pre-pregnancy values during postpartum.
Lamotrigine apparent oral clearance may increase by as much as 150% during the second and third trimesters and there are indications that women treated with this agent may experience increased seizure frequency. Lamotrigine oral clearance appears to return to baseline values during the early post-partum period which will likely necessitate further dose modifications. These observations support the notion of monitoring lamotrigine serum concentrations both during pregnancy as well as post-partum.
A well-defined serum concentration effect for lamotrigine has yet to be conclusively established, but the target range of 4-14 has been suggested for patients with epilepsy.
Lamotrigine displays substantial variability between patients with regards to its elimination from the body. Its half life is reduced by approximately 50%, about 12-15 hours in the presence of antiepileptic-inducing medications such as carbamazepine, Phenobarbital, primidone and phenytoin. There does not appear to be any significant interactions between lamotrigine and newer antiepileptic drugs such as topiramate, felbamate, gabapentin, pregabalin, zonisamide, vigabatrin and levetiracetam. Pharmacokinetic interactions between lacosamide and lamotrigine would not be expected. There have been modest reductions in the concentration of lamotrigine in patients who receive oxcarbazepine or Trileptal.
Because lamotrigine does not undergo enzyme-dependent metabolism, drugs that inhibit certain enzymes in the liver that affect lamotrigine can affect the concentration of the drug. Valproic acid can decrease lamotrigine’s clearance and it results in increased plasma concentrations. Valproic acid markedly reduces lamotrigine clearance and prolongs the half life to about 60 hours. Recent studies in adults have suggested that the maximal inhibition of lamotrigine clearance by valproic acid is approximately 65% with 50% of maximal inhibition occurring at valproic concentration of about 5-6 micrograms/mL. These studies suggest a valproic-mediated inhibition of lamotrigine begins at low valproic doses with maximal inhibition occurring at valproic doses of approximately 500 mg per day. While earlier studies suggested that concurrent treatment with lamotrigine may result in modestly decreased valproic serum concentration, this is unlikely to be important clinically.
Lamotrigine does not induce or inhibit cytochrome P450 isoenzymes. It is not extensively bound to plasma proteins. These properties would predict that lamotrigine have a low incidence of causing important pharmacokinetic interactions. Lamotrigine does not appear to significantly alter hormone concentrations in females who are taking oral contraceptives.
Daily doses of acetaminophen unexpectedly increase lamotrigine clearance. Occasional use of acetaminophen would not be expected to alter lamotrigine pharmacokinetics; however, prolonged dosage could. While Lamictal does not alter the pharmacokinetics of oral contraceptive medications, recent studies have suggested that treatment with lamotrigine and combined oral contraceptives may decrease lamotrigine serum concentrations. The addition of an oral contraceptive which contains ethinyl estradiol may decrease lamotrigine concentrations by as much as 50%. Importantly, this interaction dissipates quite rapidly during the pill-free week and within one week following discontinuation of an oral contraceptive agent.
Lamotrigine has the following FDA indications:
- Partial seizures
- Primary generalized tonic-clonic seizures
- Generalized seizures of Lennox-Gastaut syndrome
The newer extended-release formulation is FDA approved as adjunctive treatment for partial seizures in patients greater than 13 years of age. In addition, lamotrigine is indicated for conversion to monotherapy in adults more than 16 years of age with partial seizures who are receiving treatment with carbamazepine, phenytoin, Phenobarbital, primidone, or valproic acid as a single background AED. To date, although data from several United States and European clinical trials suggest its usefulness, lamotrigine is not approved by the FDA as an initial monotherapy agent.
Seven pre-marketing, multi-center, double-blind placebo-controlled add-on trials support the usefulness of Lamictal as adjunctive treatment for partial seizures in adults. The study with the highest dose demonstrated a mean reduction in seizure frequency of 36% compared to baseline. Seizure frequency was reduced by greater than 50% in about a quarter of these patients. More recently, a study found that once-daily extended-release lamotrigine was as effective as a combination therapy in patients 13 years and older with partial seizures, many of whom had failed multiple other AEDs. In this study, the percentage of patients with at least a 50% reduction in seizure frequency was significantly greater than placebo.
Although the lamotrigine is approved as a conversion to monotherapy, it is not approved as initial monotherapy treatment. Efficacy as a monotherapy in partial seizures has been shown by multicenter, double-blind randomized trials comparing 500 mg of lamotrigine to an active control of 1000 mg of valproic acid. Similarly, lamotrigine has been shown to have comparable effectiveness when compared to controlled-release carbamazepine in newly diagnosed older patients with epilepsy. A recently published SANAD trial, an unblinded, randomized effectiveness trial conducted in the United Kingdom suggested that lamotrigine was at least as effective as carbamazepine in patients with newly diagnosed partial seizures. Patients treated with lamotrigine were found to have a significantly longer time to treatment failure than either gabapentin or topiramate.
Lamotrigine does have an approval for generalized seizures in Lennox-Gastaut syndrome. A large, multi-center, double-blind, randomized add-on trial of lamotrigine demonstrated efficacy of lamotrigine for treatment of major motor seizures in children and young adults with Lennox-Gastaut syndrome. The target dose of lamotrigine was 15 mg/kg/patient not taking valproate, and 5 mg/kg for those taking valproic acid. Major motor seizures defined as atonic, tonic, major myoclonic, and tonic-clonic were reduced by 32% compared to baseline. Only a 9% reduction was seen in the placebo group. This led to its approval for Lennox-Gastaut syndrome major motor seizures.
Lamotrigine does not have an FDA approval for treatment of idiopathic generalized epilepsy; however, trials have suggested that lamotrigine may be effective for primary generalized epilepsy. Curiously, however, there is a belief that lamotrigine may actually exacerbate myoclonus. A small case series suggested that myoclonus may worsen with lamotrigine treatment in some patients with idiopathic generalized epilepsy.
Lamotrigine is indicated for the maintenance treatment of bipolar disorder to delay the time to occurrence of mood episodes such as depression, mania, hypomania in adults 18 years of age or older. The effectiveness of lamotrigine in the acute treatment of mood episodes has not been established. Further trials are ongoing to evaluate its usefulness.
Similar to efficacy, the safety profile of Lamictal has been defined by numerous clinical studies. The most important side effect has been rash. The mechanism for this rash is unknown, but it may be genetic. There is a cross-reactivity for rash with other anti-epileptic medication, especially carbamazepine and phenytoin. The incidence of serious rash associated with hospitalization, especially in pediatric patients was 0.8%. In adult populations, serious rash associated with lamotrigine occurred in 0.3%. In clinical trials in patients with bipolar disorders, there was a 0.08% rash rate. In general, the risk for serious rash appears to be increased when lamotrigine was either initiated at too high a dose or when dosage is rapidly increased.
With regards to comparison with other anti-epileptic drugs, there is no difference in rash rates between lamotrigine, carbamazepine and phenytoin. The most common side effects that are noted with lamotrigine include dizziness, some nausea, insomnia, tremor and rash. Several double-blind randomized studies indicate that lamotrigine may cause significantly less sedation than most other anti-epileptic drugs. Some studies have suggested that lamotrigine has a favorable psychotropic profile and may improve mood in some patients. This observation is confounded by increased sedation and improved concentration after converting from less well tolerated anti-epileptic drugs, but available evidence supports that lamotrigine can improve mood or even protect against adverse mood effects of other medications.
In summary, lamotrigine has been found to be a very popular drug primarily because it is one of the few broad-spectrum medications that can cover a number of seizures types and complex epilepsy conditions. The fact that it has been shown to be effective for a number of seizures explains why so many individuals have chosen to initiate this drug in their patients with epilepsy. The main adverse effect reported with the medication is that of rash and if one follows the slow titration escalation as suggested by the manufacturers of the drug, then one is less likely to see rash. However, that has been one of the difficulties in the use of this drug is that one has to give about 5 to 6 weeks of time in order to increase the dose of the drug to a therapeutic level.
More importantly is the fact that lamotrigine is a complicated drug to use with drugs such as Depakote where Depakote actually increases the chance of lamotrigine toxicity and therefore one has to be careful when adding lamotrigine to Depakote. Lastly, oral contraceptive agents that contain estrogen may lower the concentration of lamotrigine, so careful risk has to be taken with the use of this medication.
In women with epilepsy, lamotrigine has recently been found to have some effects that can occur in women who are exposed to the drug during their pregnancy. It is considered a Category C drug, which means that it may potentially lead to teratogenic effects in women exposed to this drug. The North American Anti-epileptic Drug Pregnancy Registry (NAAED) reported an unexpectedly high prevalence of isolated non-syndromic cleft palate and/or cleft lip in infants exposed to lamotrigine monotherapy during the first trimester of pregnancy. Because of this, lamotrigine has been assigned to pregnancy Category C by the FDA. Animal studies have revealed maternal toxicity and secondary fetal toxicity producing reduced fetal weight, delayed ossification and fetal death.
With regards to breast feeding, lamotrigine has been detected in human milk. Mild thrombocytosis is reported in the breast-fed infant. The manufacturer does not recommend breast feeding while taking lamotrigine.
In conclusion, lamotrigine continues to be a popular choice for physicians due to its favorable safety and effectiveness profile. It can cause problems such as rash, insomnia and it does improve mood. The negatives in the choice of this drug include the fact that it is slow to titrate and one must be very careful about its drug interactions with drugs such as valproic acid.
Read detailed information about lamotrigine in our seizure medicines section
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The Epilepsy Therapy Project is committed to funding projects that will lead to new therapies which can be quickly brought to the individual with epilepsy. Through our epilepsy.com website, we hope to educate all of our readers about the various treatments that are available for seizures and epilepsy in the hope that some improved quality of life can occur. Our commitment to the discovery of new treatments will hopefully help to improve upon medications such as Lamictal or creation of novel choices of treatment that may help to stop seizures.
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Hallway Conversations, a series of audio podcasts in which Dr. Joseph Sirven, Editor-in-Chief of epilepsy.com, has the pleasure of having a brief conversation with thought leaders and newsmakers in the field of epilepsy on a range of seizure related topics. The series is intended as a second opinion to help clinicians understand the latest research as explained by the investigator or perhaps focus on a clinical issue with the help of a leading epilepsy authority on the topic. The purpose is to frame the latest epilepsy news in the right context so as to better manage patients with seizures and improve quality of life. We hope that you find the series informative and helpful and that you join us in listening on a regular basis.
Listen to the latest podcasts in the Hallway Conversations series from:
September 14, 2011
Daniel J. Curry, MD
Director of Pediatric Surgical Epilepsy and Functional Neurosurgery
Texas Children's Hospital
Assistant Professor of Neurological Surgery
Baylor College of Medicine
Topic: Visualase surgical technique for epilepsy
September 7, 2011
Marcio A. Sotero de Menezes, MD
Director, Pediatric Epilepsy/Neurology, Genetic Epilepsy Clinic
Swedish Neuroscience Institute
Clinical Associate Professor in Neurology
University of Washington
Topic: Genetic Epilepsies due to SCN1 mutations
August 16, 2011
Ilo Leppik, MD
Topic: The Drug Resistant Epilepsy Patient
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